Chemistry:Labetalol

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Labetalol is a medication used to treat high blood pressure and in long term management of angina.[1][2] This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy.[2] In essential hypertension it is generally less preferred than a number of other blood pressure medications.[1] It can be given by mouth or by injection into a vein.[1]

Common side effects include low blood pressure with standing, dizziness, feeling tired, and nausea.[1] Serious side effects may include low blood pressure, liver problems, heart failure, and bronchospasm.[1] Use appears safe in the latter part of pregnancy and it is not expected to cause problems during breastfeeding.[2][3] It works by blocking the activation of β- and α-adrenergic receptors.[1]

Labetalol was patented in 1966 and came into medical use in 1977.[4] It is available as a generic medication.[2] In 2023, it was the 232nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[5][6]

Medical uses

Labetalol is effective in the management of hypertensive emergencies, postoperative hypertension, pheochromocytoma-associated hypertension, and rebound hypertension from beta blocker withdrawal.[7]

It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia.[8]

It is also used as an alternative in the treatment of severe hypertension.[7]

Labetalol is useful in the treatment of acute cardiovascular toxicity (e.g. in overdose) caused by sympathomimetics like amphetamine, methamphetamine, cocaine, ephedrine, and pseudoephedrine.[9][10] Other beta blockers are also used.[9][10] However, the controversial yet possible phenomenon of "unopposed α-stimulation" with administration of selective beta blockers to block non-selective sympathomimetics potentially makes dual alpha-1 and beta blockers like labetalol and carvedilol more favorable for such purposes.[9][10] The rate of unopposed α-stimulation with selective beta blockers has been reported to be 0.4%,[9] whereas no cases of unopposed α-stimulation have been reported with dual alpha and beta blockers like labetalol.[10]

Special populations

Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women.[11]

Nursing: breast milk has been shown to contain small amounts of labetalol (0.004% original dose). Prescribers should be cautious in the use of labetalol for nursing mothers.[11]

Pediatric: no studies have established safety or usefulness in this population.[11]

Geriatric: the elderly are more likely to experience dizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect.[11]

Contraindications

Labetalol is contraindicated in people with overt cardiac failure, greater-than-first-degree heart block, severe bradycardia, cardiogenic shock, severe hypotension, anyone with a history of obstructive airway disease including asthma, and those with hypersensitivity to the drug.[12]

Side effects

Common

Low blood pressure with standing is more severe and more common with IV formulation (58% vs 1%[11]) and is often the reason larger doses of the oral formulation cannot be used.[13]

Rare

Pharmacology

Mechanism of action

Labetalol is a beta blocker, or an antagonist of the β-adrenergic receptors. It is specifically a non-selective antagonist of the β1- and β2-adrenergic receptors.[15] Labetalol has intrinsic sympathomimetic activity.[15] It is also an antagonist of the α1-adrenergic receptor, and hence is additionally an alpha blocker. The antagonism of the adrenergic receptors by labetalol is competitive against other catecholamines[16] and its actions on the receptors are potent and reversible.[12] Labetalol acts by blocking α- and β-adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output.

Labetalol is about equipotent in blocking β1- and β2-adrenergic receptors.[17] The amount of α to β blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of α to β blockade is 1:3.[18][19] Intravenously, α to β blockade ratio is 1:7.[17][12] Thus, labetalol can be thought to be a beta blocker with some α-blocking effects.[12][16][20] By comparison, labetalol is a weaker β-adrenergic receptor blocker than propranolol, and has a weaker affinity for α-adrenergic receptors compared to phentolamine.[17][16]

Labetalol's dual α- and β-adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasing systemic vascular resistance with little effect on stroke volume, heart rate and cardiac output.[21] During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume.[22]

Labetalol possesses significant intrinsic sympathomimetic activity (ISA).[23][20] In particular, it is a partial agonist at β2-adrenergic receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial β2-adrenergic receptor agonism and through α1-adrenergic receptor blockade.[20][24] Overall, this vasodilatory effect can decrease blood pressure.[25] It was originally reported to lack ISA, but a slight degree of activity was subsequently characterized.[23]

Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity.[23][20][26] By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity.[27]

Physiological action

The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking β1-adrenergic receptors should decrease heart rate, but labetalol does not. When labetalol is given in acute situations, it decreases the peripheral vascular resistance and systemic blood pressure while having little effect on the heart rate, cardiac output and stroke volume, despite its α1-, β1- and β2-adrenergic receptor blocking mechanism.[21][22] These effects are mainly seen when the person is in the upright position.[25]

Long term labetalol use also has different effects from other beta blockers. Other beta blockers, such as propranolol, persistently reduce cardiac output during exercise. The peripheral vascular resistance decreases when labetalol is first administered. Continuous labetalol use further decreases peripheral vascular resistance. However, during exercise, cardiac output remains the same due to a compensatory mechanism that increases stroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume.[22]

Pharmacokinetics

Distribution

Labetalol is often classified as a beta blocker with low lipophilicity and hence lower potential for crossing the blood–brain barrier and blood–placenta barrier.[15][28][29] This in turn may result in fewer effects in the central nervous system as well as a lower risk of neuropsychiatric side effects.[15] Paradoxically however, labetalol actually shows high lipophilicity.[30][31][32][33][34][23] In any case, labetalol, in animals including rats, rabbits, and dogs, was found to cross into the brain in negligible amounts, probably for reasons other than low lipophilicity.[11][23][35] On the other hand, the drug has been shown to cross the blood–placenta barrier in humans.[11]

Chemistry

The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons.[36] This configuration results in strong agonist activity. As the size of the substituent attached to the amine becomes greater, particularly with respect to a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is, therefore, an antagonist.[36] Labetalol, with its 1-methyl-3-phenylpropyl substituted amine, is greater in size relative to a t-butyl group and therefore acts predominantly as an antagonist. The overall structure of labetalol is very polar. This was created by substituting the isopropyl group in the standard beta blocker structure with an aralkyl group, including a carboxamide group on the meta position, and by adding a hydroxyl group on the para position.[17]

Labetalol has two chiral carbons and consequently exists as four stereoisomers.[37] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1-adrenergic receptor blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed non-selective β-adrenergic receptor blocker and selective α1 blocker.[17] Labetalol is typically given as a racemic mixture to achieve both α- and β-adrenergic receptor blocking activity.[38]

Stereoisomers of labetalol

(R,R)-Labetalol
CAS number: 75659-07-3
(S,S)-Labetalol
CAS number: 83167-24-2

(R,S)-Labetalol
CAS number: 83167-32-2
(S,R)-Labetalol
CAS number: 83167-31-1

It is chemically designated in International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride.[38][39]

The experimental log P of labetalol is 2.7 to 3.1 and its predicted log P ranges from 1.73 to 3.1.[30][31][32][33] Hence, it has relatively high lipophilicity.[30][31][32][33][34]

History

Labetalol was the first drug created that combined both α- and β-adrenergic receptor blocking properties. It was created to potentially fix the compensatory reflex issue that occurred when blocking a single receptor subtype, i.e. vasoconstriction after blocking β-adrenergic receptors or tachycardia after blocking α-adrenergic receptors. Because the reflex from blocking the single receptor subtypes acted to prevent the lowering of blood pressure, it was postulated that weak blocking of both α- and β-adrenergic receptors could work together to decrease blood pressure.[17][22]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Labetalol Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/labetalol-hydrochloride.html. 
  2. ↑ 2.0 2.1 2.2 2.3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 147–148. ISBN 9780857113382. 
  3. ↑ "Labetalol Use During Pregnancy". https://www.drugs.com/pregnancy/labetalol.html. 
  4. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 463. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA463. 
  5. ↑ "The Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Labetalol Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Labetalol. 
  7. ↑ 7.0 7.1 "Chapter 21: Hypertensive Crises". Koda-Kimble and Young's Applied Therapeutic: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. 2013. pp. 520–535. ISBN 978-1-60913-713-7. 
  8. ↑ "Severe pre-eclampsia and hypertensive crises". Best Practice & Research. Clinical Obstetrics & Gynaecology 27 (6): 877–884. December 2013. doi:10.1016/j.bpobgyn.2013.07.003. PMID 23962474. 
  9. ↑ 9.0 9.1 9.2 9.3 "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug Alcohol Depend 150: 1–13. May 2015. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076. 
  10. ↑ 10.0 10.1 10.2 10.3 "β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon". J Cardiovasc Pharmacol Ther 22 (3): 239–249. May 2017. doi:10.1177/1074248416681644. PMID 28399647. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 "Trandate". Prometheus Laboratories Inc. November 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018716s026lbl.pdf. 
  12. ↑ 12.0 12.1 12.2 12.3 "Labetalol [package insert. Spring Valley, NY: Par Pharmaceutical; 2011."]. http://www.parpharm.com/generics/images/pdf/0122_po.pdf. 
  13. ↑ "Labetalol hydrochloride". Hospira. May 2015. http://www.hospira.com/en/images/EN-3744_tcm81-92515.pdf. 
  14. ↑ Bolognia JL, ed (2007). "Lichen planus and lichenoid dermatoses". Dermatology. St. Louis: Mosby. p. 161. ISBN 978-1-4160-2999-1. 
  15. ↑ 15.0 15.1 15.2 15.3 "Neuropsychiatric Consequences of Lipophilic Beta-Blockers". Medicina (Kaunas) 57 (2): 155. February 2021. doi:10.3390/medicina57020155. PMID 33572109. 
  16. ↑ 16.0 16.1 16.2 Adrenoceptor Antagonist Drugs IN: Basic & Clinical Pharmacology (12th ed.). San Francisco: McGraw Hill Lange Medical. 2012. pp. 151–168. ISBN 978-0-07-176401-8. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 "Labetalol and other vasodilator/Beta-blocking drugs.". Handbook of Hypertension. Amsterdam, Netherlands: Elsevier Sciences Publishing Co. 1988. pp. 246–273. ISBN 978-0-444-90469-0. 
  18. ↑ Basic and clinical pharmacology. New York: McGraw-Hill Medical. 2006. p. 170. ISBN 978-0-07-145153-6. 
  19. ↑ "Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol". British Journal of Clinical Pharmacology 3 (5): 849–855. October 1976. doi:10.1111/j.1365-2125.1976.tb00637.x. PMID 9968. 
  20. ↑ 20.0 20.1 20.2 20.3 Adrenoreceptor Antagonists IN: Modern Pharmacology with Clinical Applications (6th ed.). Baltimore, MD: Lippincott Williams & Wilkins. 2004. pp. 109–117. ISBN 978-0781737623. 
  21. ↑ 21.0 21.1 "Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects". Pharmacotherapy 3 (4): 193–219. August 1983. doi:10.1002/j.1875-9114.1983.tb03252.x. PMID 6310529. 
  22. ↑ 22.0 22.1 22.2 22.3 "Pharmacology of combined alpha-beta-blockade. I". Drugs 28 (Suppl 2): 16–34. January 1984. doi:10.2165/00003495-198400282-00003. PMID 6151889. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects". Pharmacotherapy 3 (4): 193–219. 1983. doi:10.1002/j.1875-9114.1983.tb03252.x. PMID 6310529. 
  24. ↑ "Hemodynamic effects of beta-blocking compounds possessing vasodilating activity: a review of labetalol, prizidilol, and dilevalol". Journal of Cardiovascular Pharmacology 11 (Suppl 2): S12–S17. 1 January 1988. doi:10.1097/00005344-198800000-00004. PMID 2464093. 
  25. ↑ 25.0 25.1 "Pharmacology of combined alpha-beta-blockade. II. Haemodynamic effects of labetalol". Drugs 28 (Suppl 2): 35–50. 1 January 1984. doi:10.2165/00003495-198400282-00004. PMID 6151890. 
  26. ↑ Toxicology in Emergency Cardiovascular Care IN: The Textbook of Emergency Cardiovascular Care and CPR. Philadelphia, PA: Lippincott Williams & Wilkins. 2009. pp. 443–452B. ISBN 978-0-7817-8899-1. 
  27. ↑ Elsevier Comprehensive Guide to Postgraduate Medical Entrance Examinations (PGMEE). 2. Elsevier India. 1 January 2009. pp. 449–. ISBN 978-81-312-1620-0. https://books.google.com/books?id=t9ZXqSXOUbsC&pg=PA449. 
  28. ↑ "Clinical pharmacokinetics and kinetic-dynamic relationships of dilevalol and labetalol". Clin Pharmacokinet 21 (2): 95–109. August 1991. doi:10.2165/00003088-199121020-00002. PMID 1884570. 
  29. ↑ "A systematic review of nicardipine vs labetalol for the management of hypertensive crises". Am J Emerg Med 30 (6): 981–993. July 2012. doi:10.1016/j.ajem.2011.06.040. PMID 21908132. 
  30. ↑ 30.0 30.1 30.2 "Labetalol". https://pubchem.ncbi.nlm.nih.gov/compound/3869. 
  31. ↑ 31.0 31.1 31.2 "Labetalol: Uses, Interactions, Mechanism of Action". 1 August 1984. https://go.drugbank.com/drugs/DB00598. 
  32. ↑ 32.0 32.1 32.2 "C19H24N2O3". 21 July 2022. https://www.chemspider.com/Chemical-Structure.3734.html. 
  33. ↑ 33.0 33.1 33.2 "Human Metabolome Database: Showing metabocard for Labetalol (HMDB0014736)". 6 September 2012. https://hmdb.ca/metabolites/HMDB0014736. 
  34. ↑ 34.0 34.1 "An investigation of the comparative liposolubilities of beta-adrenoceptor blocking agents". J Pharm Pharmacol 33 (3): 172–173. March 1981. doi:10.1111/j.2042-7158.1981.tb13743.x. PMID 6116760. 
  35. ↑ Pharmacology of Antihypertensive Therapeutics. Springer Science & Business Media. 6 December 2012. pp. 147–. ISBN 978-3-642-74209-5. https://books.google.com/books?id=kVzsCAAAQBAJ&pg=PA147. 
  36. ↑ 36.0 36.1 "Adrenergics and Cholinergic their Biosynthesis, Metabolism and Structure Activity Relationships". Medicinal Chemistry of the Peripheral Nervous System. PharmaXChange.info. 2007. http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html. Retrieved 16 October 2010. 
  37. ↑ "The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers". British Journal of Pharmacology 104 (4): 823–828. December 1991. doi:10.1111/j.1476-5381.1991.tb12513.x. PMID 1687367. 
  38. ↑ 38.0 38.1 Robertson D, Biaggioni, I. Adrenoceptor Antagonist Drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. San Francisco, CA: McGraw Hill Lange Medical; 2012: 151–168. ISBN 978-0-07-176401-8.
  39. ↑ "labetalol | C19H24N2O3". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/labetalol#section=Top. 



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